The long-term goal of the proposed study is to improve the effectiveness of smoking cessation treatment, with a specific focus on menthol cigarette smokers. In the United States, approximately 47 million adults are current cigarette smokers, and 30% of them smoke menthol cigarettes. Menthol cigarettes are particularly popular among African American smokers (ca. 70% menthol cigarette smokers). Nicotine dependence, maintained mainly by tobacco smoking, is a chronic relapsing disorder that constitutes one of the leading preventable causes of death in developed countries. In the United States, smoking-attributable health care expenditures and productivity losses exceed $190 billion annually. Smoking is highly addictive, and the efficacy of available smoking cessation treatments is very low. Future progress in this area clearly depends on a better understanding of the detailed mechanisms that underlie smoking addiction. Although overall evidence remains inconclusive, some studies suggest that menthol cigarette smoking may be associated with higher risks of lung cancer and lower quitting rates compared with nonmenthol cigarette consumption. It has been posited that menthol in cigarettes may promote the diffusibility and permeability of nicotine across the lungs and increase the depth of smoke inhalation (Report of Surgeon General, 1998). Theoretically, all of these effects of cigarette mentholation may result in increases in brain nicotine accumulation during smoking. Based on these considerations, we hypothesize that smoking menthol cigarettes will result in a higher rate of brain nicotine accumulation than smoking nonmenthol cigarettes, regardless of smokers'brand preferences. Because the rate of delivery of nicotine into the brain is known to be crucial for its reinforcing effects, verification of this hypothesis would provide a key explanation for the enhanced addictive properties of menthol cigarettes. To address our hypothesis, we propose to use a technique recently established in our laboratory, which involves positron emission tomography (PET) with 3-sec temporal resolution and cigarettes loaded with 11C-labeled nicotine. Using a cross-over design, we will scan 20 dependent (10 menthol and 10 nonmenthol) cigarette smokers twice in a counter-balanced order, once as they inhale a single puff of smoke from a menthol cigarette and the other time while they inhale from a nonmenthol cigarette. To our knowledge, the proposed study will be the first one in which the impact of cigarette mentholation on brain nicotine kinetics is directly assessed. Results from these experiments will contribute to our understanding of the neuropharmacological mechanisms underlying menthol cigarette dependence, and ultimately to the development of more effective smoking cessation treatment and prevention strategies, and to the improvement of health outcomes associated with smoking menthol cigarettes in ethnic minority populations. PUBLIC HEALTH RELEVANCE: This research will assess whether menthol alters pharmacokinetics of brain nicotine accumulation from cigarette smoking. The findings will advance our understanding of the roles of menthol in nicotine addiction and of smoking-related health disparities in ethnic minority populations, and will inform new preventive and treatment strategies.